INTRODUCTION — Carnitine deficiency may be a significant problem in patients with kidney disease, particularly in those undergoing maintenance dialysis. A discussion of carnitine metabolism, as well as the role of carnitine supplementation in this patient population, is presented in this topic review.
Carnitine deficiency in patients with inherited carnitine cycle disorders is discussed elsewhere in the following topic reviews:
●(See "Specific fatty acid oxidation disorders", section on 'Carnitine cycle defects'.)
ROLE OF CARNITINE IN INTERMEDIARY METABOLISM — Carnitine is an important intermediary in fat metabolism. It is required to shuttle long-chain fatty acids, in the form of acylcarnitines, into mitochondria for beta-oxidation (figure 1); carnitine is, therefore, crucial for energy production in tissues dependent upon fatty acid oxidation, such as cardiac and skeletal muscle. (See "Specific fatty acid oxidation disorders", section on 'Carnitine cycle defects'.)
Reactions of carnitine with activated fatty acids (acyl CoA) are esterifications of the general form:
acyl CoA + carnitine → acylcarnitine + CoASH
and are catalyzed by a family of carnitine acyltransferases.
Besides fatty acid oxidation, functions of carnitine include modulating the concentration of CoA, scavenging toxic acyl groups, and facilitating their transport out of mitochondria. Impaired fatty acid metabolism and consequent accumulation of acyl CoA are characteristic of kidney failure. Acyl CoAs inhibit numerous enzymes important in intermediary metabolism and thereby increase insulin resistance, apoptosis, generation of free radicals, and lipid peroxidation products. Conversion of acyl CoA to acylcarnitine and transport out of mitochondria constitutes a normal scavenger system for toxic acyl groups that are generated in excess in kidney failure [1-4].
KIDNEY HANDLING AND METABOLISM OF CARNITINE IN KIDNEY FAILURE — While carnitine is derived from red meat and dairy products in the diet, biosynthesis in the liver, kidney, and brain is adequate to meet normal requirements in healthy individuals. Approximately 95 percent of carnitine is stored in muscle, where it is concentrated by a specific transporter. Free carnitine is filtered at the glomerulus, and over 90 percent undergoes tubular reabsorption. By contrast, renal tubular absorption of acylcarnitine is limited, and clearance of acylcarnitine is four to eight times greater than that of free carnitine [3]. Such differential clearance is consistent with the concept that esterification with carnitine is a pathway for detoxification and elimination of toxic acyl groups.
Alterations in chronic kidney disease — In chronic kidney disease (CKD), clearance of both free carnitine and acylcarnitine is reduced. Plasma levels of free and total carnitine are unchanged, but serum acylcarnitine rises in inverse relation to the decline of the glomerular filtration rate (GFR) [5]. The ratio of acylcarnitine to free carnitine is markedly increased.
Metabolism in hemodialysis — In hemodialysis patients, plasma total carnitine concentration is normal or elevated; the free carnitine concentration is reduced (19.2 to 32.4 micromol/L) and significantly lower than in healthy controls (40 to 50 micromol/L) or in CKD; the acylcarnitine concentration is markedly increased, and the ratio of acyl to free carnitine (AC:FC) is markedly increased (0.77 to 0.96) compared with healthy controls (0.15 to 0.25) [4,6].
Several factors contribute to this abnormal profile [3-5]:
●Loss of renal parenchyma removes a source of endogenous carnitine synthesis.
●Low dietary intake of meat and dairy products deprives patients of a rich source of carnitine.
●Hemodialysis removes free carnitine and acylcarnitine. Although total dialytic removal is probably comparable with normal urinary excretion, free carnitine clearance by hemodialysis is greater than that of acylcarnitine. This pattern is the reverse of normal urinary carnitine excretion.
●Fatty acid metabolism is impaired in kidney failure. Thus, incompletely metabolized acyl residues accumulate and drive the formation of acylcarnitine esters.
●The normal preferential renal excretion of acylcarnitine is lost in kidney failure.
Metabolism in peritoneal dialysis — Metabolism of carnitine in peritoneal dialysis patients has not been sufficiently studied. Available information indicates that total and free plasma carnitine are normal, and plasma acylcarnitine is elevated.
Carnitine deficiency and dialysis patients — An AC:FC ratio >0.4 indicates a disorder of fatty acid metabolism [4,6]. Excessive generation of acyl moieties because of incomplete fatty acid oxidation enhances formation of acylcarnitines and uses up free carnitine; thus, a high AC:FC ratio and free carnitine deficiency may be a consequence as well as a cause of abnormal fatty acid metabolism. Conversion to intensive (nocturnal) hemodialysis (five to six sessions per week, eight hours per treatment) reduced free and acylcarnitine levels and improved (reduced) the AC:FC ratio [7]. This improvement could be due to amelioration of impaired fatty acid oxidation.
Effective carnitine deficiency exists if free carnitine is inadequate to meet metabolic needs; such carnitine deficiency further impairs fatty acid oxidation. However, the plasma carnitine profile does not predict whether effective carnitine deficiency exists. The vast majority (95 percent) of hemodialysis patients have low free plasma carnitine, but neither plasma total, free, or acylcarnitine nor their ratios predict clinical response to L-carnitine supplements [8,9]. By comparison, tissue (muscle or erythrocyte) total carnitine levels sometimes correlate with clinically significant endpoints.
L-carnitine supplementation increases plasma total, free, and acylcarnitine levels; the AC:FC ratio falls (improves) only moderately and incompletely, suggesting that carnitine continues to bind acyl residues that are present in excess in dialysis patients [8].
The decline of free carnitine levels depends upon dialysis vintage. In a study of 21 patients, plasma L-carnitine levels principally decreased within the first few months of beginning hemodialysis, while levels in muscle continued to decline, even after one year of dialysis [10]. These findings are consistent with a pharmacokinetic model of L-carnitine in patients receiving hemodialysis [11].
CLINICAL FEATURES OF CARNITINE DEFICIENCY — Much of our knowledge of the consequences of carnitine deficiency comes from inherited cases in children. In these children without kidney disease, the features of carnitine deficiency include muscle weakness, acute encephalopathy, hepatic dysfunction, cardiomyopathy, nonketotic hypoglycemia, frequent infections, and failure to thrive. (See "Metabolic myopathies caused by disorders of lipid and purine metabolism", section on 'Carnitine cycle disorders'.)
Carnitine deficiency in dialysis patients has been termed dialysis-related carnitine deficiency (DCD); it is distinguished from primary and secondary carnitine deficiency syndromes on the grounds that:
●Carnitine deficiency in DCD is relative and due to disparity between carnitine availability and metabolic needs.
●The ratio of acylcarnitine to free carnitine is increased.
●Symptomatic improvement requires pharmacologic doses rather than physiologic replacement.
CARNITINE SUPPLEMENTATION IN DIALYSIS PATIENTS — It is difficult to attribute benefits to L-carnitine supplementation in dialysis patients because of the following:
●The symptoms of carnitine deficiency (including muscle weakness and cardiomyopathy) overlap with those of dialysis patients generally.
●Laboratory evidence of abnormal carnitine metabolism is ubiquitous in this population.
●The response to carnitine supplementation cannot be predicted from plasma carnitine profiles.
There are numerous studies supporting the view that L-carnitine supplementation improves the plasma lipid profile, exercise capacity and oxygen utilization, muscle strength, intradialytic symptoms, sense of well-being, hospitalization rate, inflammatory markers, protein metabolism, left ventricular hypertrophy and cardiac function, anemia, and response to erythropoietin. In many of these instances, the physiologic rationale for administration of L-carnitine is appealing.
However, data evaluating these possible benefits of L-carnitine supplementation in hemodialysis patients are limited, with many trials being uncontrolled and small in size. Although some controlled, prospective studies have been performed, trials have been limited by small size, inclusion of patients independent of signs and symptoms of carnitine deficiency, and relatively short follow-up [8,9].
In general, a growing literature supports benefits with L-carnitine supplementation on inflammation and muscle wasting. However, the evidence is unclear that L-carnitine supplementation in dialysis patients improves exercise capacity, cardiomyopathy, or intradialytic symptoms.
Protein and muscle catabolism and signs of inflammation — Carnitine deficiency may contribute to muscle wasting in dialysis patients [4].
Conversely, supplementation with L-carnitine may have beneficial effects on inflammation, the oxidative state, and protein metabolism among dialysis patients. This is suggested by multiple small trials that have demonstrated improvement in the following surrogate parameters with oral or intravenous carnitine supplementation [9,12-16]:
●Increase in:
•Muscle mass, lean body weight, muscle strength, and body mass index
•Albumin, transferrin
●Reduction in:
•Blood urea nitrogen, creatinine, and phosphate
•C-reactive protein
•Serum amyloid A protein
•Skin deposition of advanced glycation end-products
Lipid metabolism — Observational studies have shown that L-carnitine supplementation increases fatty acid oxidation and reduces myocardial fatty acid retention [4]. However, this has not translated into clinically significant improvement in serum lipid profile among dialysis patients [17,18].
Exercise limitation and oxygen consumption — The ability of L-carnitine supplementation to improve exercise performance in patients receiving hemodialysis is unclear [9,19-22]. Some studies demonstrated that L-carnitine supplementation improved muscle strength but not endurance [19,20]. However, when muscle metabolism and function were assessed by magnetic resonance or near-infrared spectroscopy, L-carnitine supplementation for 16 weeks in patients receiving maintenance hemodialysis showed no effect [22].
These disparate results for the effect of L-carnitine supplementation on exercise capacity may reflect a failure to select a severely carnitine-deficient population, such as long-term dialysis patients. They also suggest that impairment of muscle energetics in some dialysis patients is due not only to carnitine deficiency, but to other defects in fatty acid metabolism, such as carnitine palmitoyl transferase deficiency.
Intradialytic complications — L-carnitine may improve cardiac and skeletal muscle energy metabolism [9]. However, whether this can lead to improvement of intradialytic symptoms is unclear; clinical trials have shown mixed results. In a 2008 meta-analysis of 193 dialysis patients, for example, L-carnitine supplementation failed to improve dialysis-related muscle cramping or intradialytic hypotension [23]. However, in a subsequent small trial of 18 hemodialysis patients, L-carnitine supplementation led to fewer episodes of intradialytic hypotension compared with placebo [24].
Quality of life — Evidence examining whether carnitine supplementation improves quality of life in dialysis patients is conflicting [9,19,25,26]. Quality of life and a sense of well-being were significantly improved in some trials [9,26], but unchanged in another study [25]. (See "Hyporesponse to erythropoiesis-stimulating agents (ESAs) in chronic kidney disease", section on 'Our approach to ESA hyporesponsiveness'.)
Hospitalization — The effect of carnitine supplementation on rates of hospitalization is unclear. Review of Centers for Medicare and Medicaid Services (CMS) administrative data for prevalent hemodialysis patients in the years 1998 to 2003 revealed that infusion of L-carnitine 1 g per session for at least 10 sessions in a month was associated with a statistically significant reduction of 10.8 percent in subsequent months' hospital days [27]. However, a causal relationship cannot be inferred. It is important to note that no existing randomized trials have addressed this issue.
Anemia and response to erythropoietin — L-carnitine may be effective in patients with chronic kidney disease (CKD) and anemia. This is discussed in detail separately. (See "Hyporesponse to erythropoiesis-stimulating agents (ESAs) in chronic kidney disease", section on 'Our approach to ESA hyporesponsiveness'.)
Cardiovascular effects — Observations of benefit from L-carnitine supplementation in trials with small numbers of patients include partial reversal of cardiomegaly, improvement of left ventricular ejection fraction, and reductions in cardiac arrhythmias and anginal episodes [28-30]. A multicenter, randomized, controlled trial showed that L-carnitine in large doses ameliorated left ventricular dilatation after myocardial infarction, but this study was not done in dialysis patients [31]. A multicenter, randomized, controlled, open-label study of 148 hemodialysis patients with carnitine deficiency showed that oral L-carnitine, 20 mg/kg/day, increased ejection fraction and reduced left ventricular mass index [32].
Oral carnitine is metabolized to trimethylamine (TMA) by gut micro-organisms, and TMA is methylated in the liver to trimethylamine-N-oxide (TMAO) [33]. TMAO levels are associated with cardiovascular risk and increased mortality [34-36], but it is not known whether TMAO is a marker or a mediator of these associations.
TREATMENT OF DIALYSIS-RELATED CARNITINE DEFICIENCY
Indications for treatment — We administer L-carnitine to dialysis patients only in limited circumstances. The major potential indication is severe and debilitating dialysis-related hypotension that is refractory to standard therapies. (See "Intradialytic hypotension in an otherwise stable patient", section on 'Prevention of recurrent episodes'.)
Several consensus conferences as well as the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) working groups that developed guidelines for nutrition and for anemia in chronic kidney disease (CKD) have suggested that L-carnitine supplementation may be considered in the following additional settings when standard therapy has not been effective [37-39]:
●Muscle weakness and lack of functional well-being (see "Uremic myopathy and deconditioning in patients with chronic kidney disease (including those on dialysis)", section on 'Treatment')
●Decreased exercise capacity or low peak oxygen consumption
●Cardiomyopathy and low cardiac output
●Anemia of kidney failure that is unresponsive to or requires large doses of erythropoietin (see "Hyporesponse to erythropoiesis-stimulating agents (ESAs) in chronic kidney disease", section on 'Our approach to ESA hyporesponsiveness')
Because of potential toxicity, absence of proof of efficacy, cost, and inability to predict benefit from laboratory evidence of carnitine deficiency in the dialysis population, we do not agree with routine use of L-carnitine in dialysis patients for these indications. However, L-carnitine may be considered for these indications if other therapy has been ineffective and if they are severe enough to risk potential toxicity.
The recommendation from NKF-KDOQI was based on the assumption that a trial of L-carnitine administration, while of unproven efficacy, would at least do no harm. However, more recent studies that have shown an association between increased cardiovascular risk and the L-carnitine metabolite trimethylamine-N-oxide (TMAO) suggest possible toxicity associated with carnitine. (See 'Cardiovascular effects' above.)
If L-carnitine supplementation is used, close follow-up and objective clinical end points are required. The NKF Carnitine Consensus Conference recommended that the clinical response to L-carnitine be evaluated at three-month intervals and the agent discontinued if no clinical improvement has occurred within 9 to 12 months [39]. In our opinion, this interval should be reduced to three to six months. Measurement of plasma carnitine levels to predict response or monitor treatment has not been useful. However, the Centers for Medical and Medicaid Services (CMS) has required a predialysis plasma-free carnitine level <40 micromol/L to qualify L-carnitine administration for reimbursement.
L-carnitine dosing, route of administration, and toxicity — Because of the toxicity of D-carnitine, racemic mixtures of D- and L-carnitine should not be used. Optimal dosing is not defined for L-carnitine. The US Food and Drug Administration (FDA) approved the use specifically of the intravenous (IV) formulation of L-carnitine in dialysis patients. A dose of 20 mg/kg IV after dialysis has been employed in several controlled trials [8,9,12,13,40] and has been recommended [37,39]. Higher doses (up to 100 mg/kg) have been used, but total doses >3 grams may increase platelet aggregation.
L-carnitine is not routinely administered in peritoneal dialysate. However, L-carnitine may be an effective glucose-sparing osmotic agent that enhances viability of mesothelial cells among peritoneal dialysis patients. In a preliminary study of four patients receiving peritoneal dialysis for five days, equimolar L-carnitine was substituted for dextrose and yielded comparable if not superior ultrafiltration [41].
Orally administered L-carnitine is not recommended, because of the following:
●High oral doses are required because of limited bioavailability [42]. In addition, data on the efficacy of oral L-carnitine are limited.
●Orally administered L-carnitine is converted to trimethylamine (TMA) by the intestinal microbiome and thence to TMAO in the liver [33-35] (see 'Cardiovascular effects' above). These toxic metabolites accumulate between dialysis sessions, even in patients who are not receiving oral L-carnitine supplements, but are efficiently cleared by dialysis [43]. In dialysis patients who receive oral L-carnitine 1 g daily, plasma concentrations of TMAO continue to rise after two weeks [44]. TMA may cause cognitive impairment and malodorous breath characteristic of uremia [45], and TMAO has been associated with major adverse cardiovascular events and mortality [34-36]. (See 'Cardiovascular effects' above.)
The safety of L-carnitine administered intravenously is not fully established. It is unknown whether a fraction of IV L-carnitine is converted to TMAO by intestinal bacteria. Such a conversion is plausible since L-carnitine does undergo enterohepatic circulation [46]. In addition, although TMAO is efficiently removed with dialysis, it is unknown whether its accumulation between dialysis sessions has any harmful effects [43].
SUMMARY AND RECOMMENDATIONS
●In hemodialysis patients, plasma total carnitine concentration is normal or elevated, and the free carnitine concentration is reduced. Although effective carnitine deficiency exists if free carnitine is inadequate to meet metabolic needs, the plasma carnitine profile does not predict whether effective carnitine deficiency exists. (See 'Kidney handling and metabolism of carnitine in kidney failure' above.)
●In children with carnitine deficiency but without kidney disease, the features of carnitine deficiency include muscle weakness, acute encephalopathy, hepatic dysfunction, cardiomyopathy, nonketotic hypoglycemia, frequent infections, and failure to thrive. Carnitine deficiency in dialysis patients (DCD) is distinguished from these carnitine deficiency syndromes in that DCD is relative and due to the disparity between carnitine availability and metabolic needs, and symptomatic improvement requires pharmacologic doses rather than physiologic replacement. (See 'Clinical features of carnitine deficiency' above.)
●It is often difficult to ascribe benefits to L-carnitine supplementation in dialysis patients. This is because the symptoms of carnitine deficiency overlap with those of dialysis patients generally, laboratory evidence of abnormal carnitine metabolism is ubiquitous, and the response to carnitine supplementation cannot be predicted from plasma carnitine profiles. (See 'Carnitine supplementation in dialysis patients' above.)
●Toxic metabolites of L-carnitine (trimethylamine [TMA] and trimethylamine-N-oxide [TMAO]) are generated by the intestinal microbiome after oral administration. Whether this occurs after intravenous (IV) administration is unknown. (See 'L-carnitine dosing, route of administration, and toxicity' above.)
●There is no strong evidence that L-carnitine supplementation in dialysis patients improves muscle wasting or weight loss, exercise capacity, cardiomyopathy, or intradialytic symptoms. Furthermore, the safety of L-carnitine has been called into question by studies of the intestinal microbiome. For most dialysis patients, we do not routinely administer L-carnitine. Exceptions may be made for dialysis patients with severe or debilitating conditions, such as dialysis-related hypotension, muscle wasting, or cardiomyopathy, that are refractory to standard therapies. (See 'Carnitine supplementation in dialysis patients' above.)
